U.S. patent application number 16/666119 was filed with the patent office on 2020-03-12 for system and/or method for glucose sensor calibration.
The applicant listed for this patent is Medtronic MiniMed, Inc.. Invention is credited to Desmond Barry Keenan, John J. Mastrototaro.
Application Number | 20200078517 16/666119 |
Document ID | / |
Family ID | 59496717 |
Filed Date | 2020-03-12 |
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United States Patent
Application |
20200078517 |
Kind Code |
A1 |
Keenan; Desmond Barry ; et
al. |
March 12, 2020 |
SYSTEM AND/OR METHOD FOR GLUCOSE SENSOR CALIBRATION
Abstract
The subject matter disclosed herein relates to systems, methods
and/or devices for calibrating sensor data to be used in estimating
a blood glucose concentration. A relationship between sensor
measurements and reference readings may be used to estimate a
relationship between sensor measurements and blood glucose
concentration. Such sensor measurements may be weighted according
to a decreasing function of uncertainty associated with sensor
values.
Inventors: |
Keenan; Desmond Barry;
(Hollywood, CA) ; Mastrototaro; John J.; (Los
Angeles, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Medtronic MiniMed, Inc. |
Northridge |
CA |
US |
|
|
Family ID: |
59496717 |
Appl. No.: |
16/666119 |
Filed: |
October 28, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15018702 |
Feb 8, 2016 |
10471207 |
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16666119 |
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12345477 |
Dec 29, 2008 |
9289168 |
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15018702 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 5/1723 20130101;
G16B 20/00 20190201; A61M 2230/005 20130101; A61B 2560/0223
20130101; A61B 5/14532 20130101; A61M 2230/201 20130101; G16H 20/17
20180101; G16H 40/63 20180101; G06F 19/3468 20130101; G16H 10/40
20180101 |
International
Class: |
A61M 5/172 20060101
A61M005/172; A61B 5/145 20060101 A61B005/145; G16H 40/63 20060101
G16H040/63; G16H 20/17 20060101 G16H020/17; G16B 20/00 20060101
G16B020/00; G16H 10/40 20060101 G16H010/40 |
Claims
1-44. (canceled)
45. A method comprising: obtaining samples of an electrical signal
generated by a sensor, said samples having sample values responsive
to a concentration of an analyte in a bodily fluid of a patient;
obtaining reference measurement values, said reference measurement
values being indicative of said concentration of said analyte in
said bodily fluid of said patient; temporally associating at least
some of said sample values with at least some of said reference
measurement values; for at least one of said sample values
temporally associated with at least one of said reference
measurement values, weighting said at least one of said temporally
associated sample values based, at least in part, on a measure of
statistical dispersion of said electrical signal, said measure of
statistical dispersion of said electrical signal being determined
based, at least in part, on said at least one of said reference
measurement values; determining one or more parameters of an
estimator of said concentration of said analyte based, at least in
part, on said weighted sample values; and displaying a level of
said analyte in said bodily fluid based, at least in part, on the
determined one or more parameters of the estimator of said
concentration of said analyte in said bodily fluid of said
patient.
46. The method of claim 45, and further comprising: generating a
control signal to a pump to affect infusion of a substance to said
patient based, at least in part, on said determined one or more
parameters of said estimator of said concentration of said analyte
in said bodily fluid of said patient.
47. The method of claim 45, wherein said concentration of said
analyte in said bodily fluid of said patient comprises a
blood-glucose concentration of said patient.
48. The method of claim 45, wherein said determining said one or
more parameters comprises determining said one or more parameters
based, at least in part, on a linear regression of said weighted
sample values and said temporally associated reference measurement
values.
49. The method of claim 45, wherein said determining said one or
more parameters of said estimator further comprises: calculating a
linear regression sensitivity ratio based, at least in part, on
said weighted sample values and temporally associated reference
measurement values; selecting an offset based, at least in part, on
said calculated linear regression sensitivity ratio; and
calculating a modified linear regression sensitivity ratio based,
at least in part, on said selected offset, said weighted sample
values and said temporally associated reference measurement
values.
50. The method of claim 45 wherein said measure of statistical
dispersion comprises a variance and/or approximation of a variance
of said sample values as a function of said temporally associated
reference measurement values.
51. The method of claim 45, wherein said at least some of said
sample values temporally associated with said at least one of said
reference measurement values to be weighted according to an inverse
of said measure of statistical dispersion of said sample
values.
52. The method of claim 45, and further comprising: estimating a
linear relationship of said measure of statistical dispersion of
said electrical signal versus analyte concentration; and deriving
said one or more parameters based, at least in part, on said linear
relationship.
53. The method of claim 45, and further comprising calibrating
measurements from said sensor for measuring said concentration of
said analyte in said bodily fluid of said patient based, at least
in part, on said determined one or more parameters.
54. An apparatus comprising: a sensor to generate one or more
electrical sensor signals responsive to a concentration of an
analyte in a bodily fluid in a body; a display device; and a
computing platform to: obtain sample values of said one or more
electrical sensor signals; obtain reference measurement values,
said reference measurement values to be indicative of said
concentration of said analyte in said bodily fluid; temporally
associate at least some of said sample values with at least some of
said reference measurement values; for at least one of said sample
values temporally associated with at least one of said reference
measurement values, weight said at least one of said temporally
associated sample values based, at least in part, on a measure of
statistical dispersion of said electrical signal, said measure of
statistical dispersion of said electrical signal to be determined
based, at least in part, on said at least one of said reference
measurement values; determine one or more parameters of an
estimator of said concentration of said analyte based, at least in
part, on said weighted sample values; and generate a signal to said
display device to display a level of said analyte in said bodily
fluid based, at least in part, on said determined one or more
parameters of said estimator of said blood-glucose
concentration.
55. The apparatus of claim 54, wherein said computing platform is
further to: generate a control signal to a pump to affect infusion
of a substance to said patient based, at least in part, on said
determined one or more parameters of said estimator of said
concentration of said analyte in said bodily fluid of said
patient.
56. The apparatus of claim 54, wherein said concentration of said
analyte in said bodily fluid of said patient comprises a
blood-glucose concentration of said patient.
57. The apparatus of claim 54, wherein said computing platform is
further to determine said one or more parameters based, at least in
part, on a linear regression of said weighted sample values and
said temporally associated reference measurement values.
58. The apparatus of claim 54, wherein said computing platform is
further to: calculate a linear regression sensitivity ratio based,
at least in part, on said weighted sample values and temporally
associated reference measurement values; select an offset based, at
least in part, on said calculated linear regression sensitivity
ratio; and calculate a modified linear regression sensitivity ratio
based, at least in part, on said selected offset, said weighted
sample values and said temporally associated reference measurement
values.
59. The apparatus of claim 54, wherein said measure of statistical
dispersion comprises a variance and/or approximation of a variance
of said sample values as a function of said temporally associated
reference measurement values.
60. The apparatus of claim 54, wherein said at least some of said
sample values temporally associated with said at least one of said
reference measurement values to be weighted according to an inverse
of said measure of statistical dispersion of said sample
values.
61. The apparatus of claim 54, wherein said computing platform is
further to: estimate a linear relationship of said measure of
statistical dispersion of said electrical signal versus analyte
concentration; and derive said one or more parameters based, at
least in part, on said linear relationship.
62. The apparatus of claim 54, wherein said computing platform is
further to calibrate measurements from said sensor to measure said
concentration of said analyte in said bodily fluid of said patient
based, at least in part, on said determined one or more
parameters.
63. An article comprising: a storage medium comprising
computer-readable instructions stored thereon which, if executed by
a computing platform are adapted to direct the computing platform
to: obtain samples sample values of one or more electrical sensor
signals, the one or more electrical sensor signals to be responsive
to a concentration of an analyte in a bodily fluid in a body;
obtain reference measurement values, said reference measurement
values to be indicative of said concentration of said analyte in
said bodily fluid; temporally associate at least some of said
sample values with at least some of said reference measurement
values; for at least one of said sample values temporally
associated with at least one of said reference measurement values,
weight said at least one of said temporally associated sample
values based, at least in part, on a measure of statistical
dispersion of said electrical signal, said measure of statistical
dispersion of said electrical signal to be determined based, at
least in part, on said at least one of said reference measurement
values; determine one or more parameters of an estimator of said
concentration of said analyte based, at least in part, on said
weighted sample values; and generate a signal to a display device
to display a level of said analyte in said bodily fluid based, at
least in part, on said determined one or more parameters of said
estimator of said blood-glucose concentration.
64. The article of claim 63, wherein the instructions, if executed
by the computing platform are further adapted to direct the
computing platform to: generate a control signal to a pump to
affect infusion of a substance to said patient based, at least in
part, on said determined one or more parameters of said estimator
of said concentration of said analyte in said bodily fluid of said
patient.
Description
BACKGROUND
Field
[0001] The subject matter disclosed herein relates to calibration
of glucose sensors for use in glucose monitoring systems, for
example.
Information
[0002] Over the years, body characteristics have been determined by
obtaining a sample of bodily fluid. For example, diabetics often
test for blood glucose levels. Traditional blood glucose
determinations have utilized a painful finger prick using a lancet
to withdraw a small blood sample. This results in discomfort from
the lancet as it contacts nerves in the subcutaneous tissue. The
pain of lancing and the cumulative discomfort from multiple needle
pricks is a strong reason why patients fail to comply with a
medical testing regimen used to determine a change in a body
characteristic over a period of time. Although non-invasive systems
have been proposed, or are in development, none to date have been
commercialized that are effective and provide accurate results. In
addition, all of these systems are designed to provide data at
discrete points and do not provide continuous data to show the
variations in the characteristic between testing times.
[0003] A variety of implantable electrochemical sensors have been
developed for detecting and/or quantifying specific agents or
compositions in a patient's blood. For instance, glucose sensors
are being developed for use in obtaining an indication of blood
glucose levels in a diabetic patient. Such readings are useful in
monitoring and/or adjusting a treatment regimen which typically
includes the regular administration of insulin to the patient.
Thus, blood glucose readings improve medical therapies with
semi-automated medication infusion pumps of the external type, as
generally described in U.S. Pat. Nos. 4,562,751; 4,678,408; and
4,685,903; or automated implantable medication infusion pumps, as
generally described in U.S. Pat. No. 4,573,994. Typical thin film
sensors are described in commonly assigned U.S. Pat. Nos.
5,390,671; 5,391,250; 5,482,473; and 5,586,553. See also U.S. Pat.
No. 5,299,571.
SUMMARY
[0004] Briefly, one embodiment relates to a method, system and/or
apparatus for obtaining samples of an electrical signal generated
by a sensor, said samples having sample values associated with
measurements of a blood-glucose concentration; individually
weighting at least some of said sample values according to a
function of blood glucose reference samples associated with said
sample values; and estimating a relationship of sample values with
said blood-glucose concentration based, at least in part, on said
individually weighted samples.
[0005] In another implementation estimating said relationship
comprises estimating a linear relationship between said sample
values and said blood-glucose concentration based, at least in
part, on a linear regression of said weighted samples and
associated blood-glucose reference values. Here, for example, such
estimating said linear relationship may further comprise
calculating a linear regression sensitivity ratio based, at least
in part, on said weighted samples and associated blood-glucose
reference values; selecting an offset based, at least in part, on
said calculated linear regression sensitivity ratio; and
calculating a modified linear regression sensitivity ratio based,
at least in part, on said selected offset, said weighted samples
and said associated blood-glucose reference values.
[0006] In another particular implementation the function of blood
glucose reference samples is based, at least in part, on a measure
of statistical dispersion of said sample values as function of
associated blood glucose reference samples. Here, for example, said
measure of statistical dispersion may comprise a variance and/or
approximation of a variance of said sample values as a function of
said associated blood glucose reference samples. Alternatively, the
function may comprise an inverse of said measure of statistical
dispersion of said sample values. In yet another alternative, the
method includes estimating a linear relationship of said measure of
statistical dispersion of said sample values versus blood glucose
concentration; and deriving the function based, at least in part,
on said linear relationship.
[0007] In another particular implementation, individually weighting
said at least some of said sample values further comprises further
weighting said samples based on how recently said samples are
obtained.
[0008] In another particular implementation, the method includes
detecting a failure of said sensor based, at least in part, on a
change in said estimated relationship.
[0009] In another particular implementation, the method includes
calibrating measurements from said sensor for measuring a
blood-glucose concentration based, at least in part, on said
estimated relationship.
[0010] In another particular implementation, individually weighting
said at least some of said sample values comprises weighting said
at least some of said sample values according to a decreasing
function of blood glucose reference values associated with said
weighted samples.
[0011] Particular embodiments may be directed to an article
comprising a storage medium including machine-readable instructions
stored thereon which, if executed by a computing platform, are
directed to enable the computing platform to execute at least a
portion of the aforementioned method according to one or more of
the particular aforementioned implementations. In other particular
embodiments, a sensor adapted generate one or more signals
responsive to a blood glucose concentration in a body while a
computing platform is adapted to perform the aforementioned method
according to one or more of the particular aforementioned
implementations based upon the one or more signals generated by the
sensor.
BRIEF DESCRIPTION OF THE FIGURES
[0012] Non-limiting and non-exhaustive features will be described
with reference to the following figures, wherein like reference
numerals refer to like parts throughout the various figures.
[0013] FIG. 1 is a is a perspective view illustrating a
subcutaneous glucose sensor insertion set and glucose monitor
device in accordance with an embodiment;
[0014] FIG. 2 is a cross-sectional view of the sensor set and
glucose monitor device as shown along the line 2--2 of FIG. 1;
[0015] FIG. 3 is a cross-sectional view of a slotted insertion
needle used in the insertion set of FIGS. 1 and 2;
[0016] FIG. 4 is a cross-sectional view as shown along line 4--4 of
FIG. 3;
[0017] FIG. 5 is a cross-sectional view as shown along line 5--5 of
FIG. 3;
[0018] FIG. 6 is a partial cross-sectional view corresponding
generally with the encircled region 6 of FIG. 2;
[0019] FIG. 7 is a cross-sectional view as shown along line 7--7 of
FIG. 2;
[0020] FIGS. 8a through 8c are diagrams showing a relationship
between sampled values, interval values and memory storage values
according to an embodiment;
[0021] FIG. 9 is a chart showing clipping limits according to an
embodiment;
[0022] FIG. 10 is a sample computer screen shot image of a post
processor analysis of glucose monitor data according to an
embodiment;
[0023] FIG. 11 is a chart illustrating the pairing of a blood
glucose reference reading with glucose monitor data according to an
embodiment;
[0024] FIG. 12 is a chart illustrating an example of a single-point
calibration according to an embodiment;
[0025] FIG. 13 is a block diagram illustrating a single-point
calibration technique according to an embodiment;
[0026] FIG. 14 is a chart illustrating an example of a linear
regression calibration according to an embodiment;
[0027] FIG. 15a is a flow diagram illustrating a calibration
process according to an embodiment;
[0028] FIG. 15b is a plot of sensor measurements versus reference
blood samples according to an embodiment;
[0029] FIG. 15c is a plot of an inverse variance of sensor
measurements versus blood glucose concentration according to an
embodiment;
[0030] FIG. 15d is a plot illustrating a linear best fit of a
standard deviation of sensor measurements versus blood glucose
concentration according to an embodiment;
[0031] FIG. 15e is a plot of a function for obtaining weights to be
applied to sensor sample values according to an embodiment;
[0032] FIG. 16 is a flowchart of a self-adjusting calibration
technique in accordance with an embodiment;
[0033] FIGS. 17a and 17b are charts illustrating an example of the
self-adjusting calibration technique according to an embodiment;
and
[0034] FIGS. 18a and 18b are further charts illustrating an example
of the self-adjusting calibration technique according to an
embodiment.
DETAILED DESCRIPTION
[0035] Reference throughout this specification to "one embodiment"
or "an embodiment" means that a particular feature, structure, or
characteristic described in connection with the embodiment is
included in at least one embodiment of claimed subject matter.
Thus, the appearances of the phrase "in one embodiment" or "an
embodiment" in various places throughout this specification are not
necessarily all referring to the same embodiment. Furthermore, the
particular features, structures, or characteristics may be combined
in one or more embodiments.
[0036] Systems for monitoring glucose in the body, for the
treatment of diabetes for example, typically employ one or more
glucose sensors to measure a blood-glucose concentration. For
example, such sensors may be adapted to generate one or more
electrical signals having a value (e.g., voltage and/or current
level) that is related to such a blood-glucose concentration. Such
a measurement of a blood-glucose concentration may then be used for
any one of several applications such as, for example, monitoring a
blood-glucose concentration for a diabetes patient.
[0037] Over time and/or with normal wear and usage of a glucose
sensor, such a relationship between a value of a signal generated
by the glucose monitoring blood sensor and actual measured blood
glucose concentration may change. Accordingly, calibration of the
signal generated by such a glucose monitoring with reference
samples of blood-glucose concentration may enable an accurate
estimate of a relationship between signal values generated by a
glucose sensor and blood-glucose concentration, leading to more
effective applications of glucose sensors and better treatment of
diabetes patients.
[0038] As shown in the drawings for purposes of illustration,
embodiments are directed to calibration methods for a glucose
monitor that is coupled to a sensor set to provide continuous data
recording of readings of glucose levels from a sensor for a period
of time. In one particular implementation, a sensor and monitor
provide a glucose sensor and a glucose monitor for determining
glucose levels in the blood and/or bodily fluids of a user.
However, it will be recognized that further embodiments may be used
to determine the levels of other body characteristics including,
for example, analytes or agents, compounds or compositions, such as
hormones, cholesterol, medications concentrations, viral loads
(e.g., HIV), bacterial levels, or the like without deviating from
claimed subject matter. In particular implementations, a glucose
sensor is primarily adapted for use in subcutaneous human tissue.
However, in still further embodiments, one or more sensors may be
placed in other tissue types, such as muscle, lymph, organ tissue,
veins, arteries or the like, and used in animal tissue to measure
body characteristics. Embodiments may record readings from the
sensor on an intermittent, periodic, on-demand, continuous, or
analog basis.
[0039] According to an embodiment, a blood glucose concentration in
fluid may be measured based upon values of a sampled sensor signal.
Also, as discussed below, it can be observed in particular
embodiments that the accuracy of such measurements used to measure
blood glucose concentration may decrease with increases in blood
glucose concentration. Accordingly, as illustrated below, in
estimating a blood glucose response of a particular sensor,
measurements taken at lower blood glucose concentrations may be
more heavily weighted than samples take a higher blood glucose
concentrations.
[0040] Briefly, in one particular embodiment, an electrical signal
generated by a sensor may be sampled to provide sample values
associated with a blood-glucose concentration. Uncertainty values
may be associated with individual ones of the measurements based,
at least in part, on blood-glucose reference values associated with
the measurements. At least some of the sample values are weighted
according to a decreasing function of uncertainty values associated
with the sample values. A relationship of sample values with
blood-glucose concentration may then be determined based, at least
in part, on the individually, weighted sample values. It should be
understood, however, this is merely an example embodiment and
claimed subject matter is not limited in this respect.
[0041] FIGS. 1-7 illustrate a glucose monitor system 1 for use with
calibration methods described herein. Glucose monitor system 1, in
accordance with one particular implementation, includes a
subcutaneous glucose sensor set 10 and a glucose monitor 100. Here,
glucose monitor 100 may be of the type described in U.S. Patent
Application Ser. No. 60/121,664, filed on Feb. 25, 1999, entitled
"Glucose Monitor System." In alternative embodiments, the glucose
monitor is of the type described in U.S. Pat. No. 7,324,012.
[0042] In one particular application, glucose monitor 100 may be
worn by a user while connected to a surface mounted glucose sensor
set 10 attached to the user's body by an electrically conductive
cable 102, of the type described in U.S. Patent Application Ser.
No. 60/121,656, filed on Feb. 25, 1999, entitled "Test Plug and
Cable for a Glucose Monitor." In one embodiment, a sensor interface
may be configured in the faun of a jack to accept different types
of cables that provide adaptability of the glucose monitor 100 to
work with different types of subcutaneous glucose sensors and/or
glucose sensors placed in different locations of a user's body.
However, in alternative embodiments, such a sensor interface may be
permanently connected to the cable 102. In additional alternative
embodiments, a characteristic monitor may be connected to one or
more sensor sets to record data of one or more body characteristics
from one or more locations on or in a user's body.
[0043] According to an embodiment, glucose sensor set 10 may be of
a type described in U.S. Patent Application Ser. No. 60/121,655,
filed on Feb. 25, 1999, entitled "Glucose Sensor Set", or U.S.
patent application Ser. No. 08/871,831, filed on Jun. 9, 1997,
entitled "Insertion Set For A Transcutaneous Sensor." Glucose
sensor 12 may be of a type described in U.S. patent application
Ser. No. 09/101,218, filed on Feb. 25, 1999, entitled "Glucose
Sensor", or described in commonly assigned U.S. Pat. Nos.
5,390,671; 5,391,250; 5,482,473; and 5,586,553; extends from the
glucose sensor set 10 into a user's body with electrodes 20 of the
glucose sensor 12 terminating in the user's subcutaneous tissue.
See also U.S. Pat. No. 5,299,571. However, in alternative
embodiments, glucose sensor 12 may use other types of sensors, such
as chemical based, optical based, or the like. In further
alternative embodiments, sensors may be of a type that is used on
the external surface of the skin or placed below the skin layer of
the user for detecting body characteristics.
[0044] According to an embodiment, glucose monitor 100 may be
capable of recording and storing data as it is received from
glucose sensor 12, and may include either a data port (not shown)
or wireless transmitter and/or receiver (also not shown) for
transferring data to and/or from a data processor 200 such as a
computer, communication station, a dedicated processor designed
specifically to work with the glucose monitor, or the like. In a
particular implementation, glucose monitor 100 may comprise a
glucose monitor as described in U.S. Pat. No. 7,324,012.
[0045] In particular applications, glucose monitor system 1 may
reduce inconvenience by separating complicated monitoring process
electronics into two separate devices; the glucose monitor 100,
which attaches to the glucose sensor set 10; and the data processor
200, which contains the software and programming instructions to
download and evaluate data recorded by the glucose monitor 100. In
addition, the use of multiple components (e.g., glucose monitor 100
and data processor 200) may facilitate upgrades or replacements,
since one module, or the other, can be modified, re-programmed, or
replaced without requiring complete replacement of the monitor
system 1. Further, the use of multiple components can improve the
economics of manufacturing, since some components may require
replacement on a more frequent basis, sizing requirements may be
different for each module, different assembly environment
requirements, and modifications can be made without affecting the
other components.
[0046] Glucose monitor 100 may take raw glucose sensor data from
glucose sensor 12 and assess such sensor data in real-time and/or
stores it for later processing or downloading to data processor
200, which in turn may analyze, display, and log the received data.
Data processor 200 may utilize the recorded data from the glucose
monitor 100 to analyze and review a blood glucose history. In
particular embodiments, glucose monitor 100 is placed into a
com-station which facilitates downloading data to a personal
computer for presentation to a physician. Software may be used to
download such data, create a data file, calibrate the data, and
display such data in various formats including charts, forms,
reports, graphs, tables, lists and/or the like. In further
embodiments, glucose monitor system 1 may be used in a hospital
environment and/or the like.
[0047] In alternative embodiments, glucose monitor 100 may include
at least portions of the software described as contained within the
data processor 200 above. Glucose monitor 100 may further contain
software enabling calibration of glucose sensor signals, display of
a real-time blood glucose value, a showing of blood glucose trends,
activate alarms and the like. A glucose monitor with these added
capabilities is useful for patients that might benefit from
real-time observations of their blood glucose characteristics even
while they're not in close proximity to a computer, communication
device and/or dedicated independent data processor.
[0048] As shown in FIG. 2, data processor 200 may include a display
214 adapted to display calculated results of raw glucose sensor
data received via a download from glucose monitor 100. Results and
information displayed may include, but is not limited to, trending
information of a characteristic (e.g., rate of change of glucose),
graphs of historical data, average characteristic levels (e.g.,
glucose), stabilization and calibration information, raw data,
tables (showing raw data correlated with the date, time, sample
number, corresponding blood glucose level, alarm messages, and
more) and/or the like. Alternative embodiments may include an
ability to scroll through raw data. Display 214 may also be used in
conjunction with buttons (not shown) on the data processor 200,
computer, communication station, characteristic monitor and/or or
the like, to program or update data.
[0049] Glucose monitor 100 may be combined with other medical
devices to accept other patient data through a common data network
and/or telemetry system. Glucose monitor 100 may be combined with a
blood glucose meter to directly import or correlate glucose
calibration reference values such as described in U.S. patent
application Ser. No. 09/334,996, filed Jun. 17, 1999, entitled
"Characteristic Monitor With A Characteristic Meter and Method Of
Using The Same." Glucose monitor 100 may also be combined with
semi-automated medication infusion pumps of the external type, as
described according to particular embodiments in U.S. Pat. Nos.
4,562,751; 4,678,408; and 4,685,903; or automated implantable
medication infusion pumps, as described according to particular
embodiments in U.S. Pat. No. 4,573,994. Glucose monitor 100 may
record data from the infusion pumps and/or may process data from
both the glucose sensor 12 and an infusion pump to establish a
closed loop system to control the infusion pump based, at least in
part, on glucose sensor measurements. In other embodiments, other
body characteristics are monitored, and the monitor may be used to
provide feedback in a closed loop system to control a drug delivery
rate. In further alternative embodiments, glucose monitor 100 can
be combined with a glucose sensor set 10 as a single unit.
[0050] Glucose sensors may be replaced periodically to avoid
infection, decaying enzyme coating and therefore sensor
sensitivity, deoxidization of the electrodes, and/or the like.
Here, a user may disconnect glucose sensor set 10 from cable 102
and glucose monitor 100. A needle 14 may be used to install another
glucose sensor set 10, and then the needle 14 may be removed.
Further description of the needle 14 and sensor set 10 according to
particular embodiments may be found in U.S. Pat. Nos. 5,586,553;
6,368,141 and 5,951,521.
[0051] A user may connect connection portion 24 of glucose sensor
set 10 through cable 102 to glucose monitor 100, so that glucose
sensor 12 can then be used over a prolonged period of time. An
initial reading may be downloaded from the glucose sensor set 10
and glucose monitor 100 to data processor 200, to verify proper
operation of glucose sensor 10 and glucose monitor 100. In
particular embodiments, glucose sensor set 10 may provide data to
glucose monitor 100 for one to seven days before replacement.
Glucose sensors 12 may last in the user's body for longer or
shorter periods of time depending on the quality of the
installation, cleanliness, the durability of the enzyme coating,
deoxidization of the sensor, user's comfort, and the like.
[0052] After installation into the body, glucose sensor 12 may be
initialized to achieve a steady state of operation before starting
a calibration process. In a particular implementation, power
supplied by three series silver oxide 357 battery cells 110 in
glucose monitor 100 may be used to speed the initialization of
glucose sensor 12. Alternatively, other power supplies may be used
such as, different battery chemistries including lithium, alkaline,
or the like, and different numbers of batteries, solar cells, a DC
converter plugged into an AC socket (provided with proper
electrical isolation), and/or the like.
[0053] The use of an initialization process can reduce the time for
glucose sensor 12 stabilization from several hours to an hour or
less, for example. One particular initialization procedure uses a
two step process. First, a high voltage (e.g., between 1.0-1.1
volts--although other voltages may be used) may be applied between
electrodes 20 of the sensor 12 for one to two minutes (although
different time periods may be used) to allow sensor 12 to
stabilize. Then, a lower voltage (e.g., between 0.5-0.6
volts--although other voltages may be used) may be applied for the
remainder of the initialization process (e.g., 58 minutes or less).
Other stabilization/initialization procedures using differing
currents, currents and voltages, different numbers of steps, or the
like, may be used. Other embodiments may omit such an
initialization/stabilization process, if not required by a
particular body characteristic sensor or if timing is not a factor.
Alternatively, a characteristic monitor or data processor 200 may
apply an algorithm to the sensor data to determine whether initial
transients have sufficiently diminished and the sensor is at a
significantly stable state to begin calibration.
[0054] In particular embodiments, data may not be considered valid
until a sensor initialization event flag (ESI) is set in data
indicating that stabilization is complete. In one particular
implementation, stabilization may be complete after 60 minutes or
when a user enters a sensor initialization flag using one or more
buttons on the glucose monitor 100. Following completion of
stabilization/initialization, glucose monitor 100 may be calibrated
to accurately interpret readings from the newly installed glucose
sensor 12.
[0055] Beginning with the stabilization process, glucose monitor
100 may measure a continuous electrical current signal (ISIG)
generated by glucose sensor 12 in connection with a concentration
of glucose present in the subcutaneous tissue of the user's body.
In particular embodiments, glucose monitor 100 may sample the ISIG
from glucose sensor 12 at a sampling rate of once every 10 seconds,
for example, as shown in FIGS. 8a-c. Examples of sampled values are
labeled A-AD in FIG. 8a. At an interval rate of once per minute,
the highest and lowest of the sampled values (shown in FIG. 8a as
circled sampled values A, E, G, I, M, R, V, W, Y, and AB) are
ignored, and the remaining four sampled values from an interval are
averaged to create interval values (shown in FIG. 8b as values F,
R', X', and AD'). At a glucose monitor memory storage rate of once
every five minutes, the highest and lowest of the interval values
(shown in FIG. 8b as values L' and X') are ignored and the
remaining three interval values are averaged and stored in a
glucose monitor memory as memory values (shown in FIG. 8c as point
AD''). The memory values are retained in memory and may be
downloaded to data processor 200. Such memory values may be used to
calibrate glucose monitor 100 and/or post processor 200 and to
analyze blood glucose levels. The sampling rate, interval rate and
the memory storage rate may be varied as necessary to capture data
with sufficient resolution to observe transients or other changes
in the data depending on the rate at which sensor values can
change, which is affected by the sensor sensitivity, the body
characteristic being measured, the physical status of the user, and
the like. In other embodiments, all of the sampled values are
included in the average calculations of memory storage values. In
alternative embodiments, more or less sampled values or interval
values are ignored depending on the signal noise, sensor stability,
or other causes of undesired transient readings. Finally, in still
other embodiments, all sampled values and/or interval values are
stored in memory.
[0056] Clipping limits may be used to limit a signal magnitude
variation from one value to the next thereby reducing the effects
of extraneous data, outlying data points, or transients. In
particular embodiments, clipping limits may be applied to interval
values. For instance, interval values that are above a maximum
clipping limit or below a minimum clipping limit may be replaced
with the nearest clipping limit value.
[0057] In alternative embodiments, interval values that are outside
of clipping limits may be ignored and not used to calculate a
subsequent memory storage value. In particular implementations,
detection of interval values outside of clipping limits may be
considered a calibration cancellation event. In further particular
embodiments, a calibration cancellation event may be recognized if
more than one value is deemed outside of clipping limits.
(Calibration cancellation events are discussed below).
[0058] In particular embodiments, clipping limits may be shifted
after each data point. Here, clipping limits may be set to a level
based, at least in part, on an acceptable amount of change from a
previous interval value to a present interval value, which is
affected by sensor sensitivity, signal noise, signal drift, and/or
the like. In particular implementations, clipping limits may be
calculated for a current interval based on the magnitude of the
previous interval value. For example, for a previous interval value
from zero up to but not including 15 Nano-Amps, clipping limits may
be set at plus and minus 0.5 Nano-Amps about the previous interval
value. For a previous interval value from 15 Nano-Amps up to but
not including 25 Nano-Amps, clipping limits may be set at plus and
minus 3% of the previous interval value, about the previous
interval value. For a previous interval value from 25 Nano-Amps up
to but not including 50 Nano-Amps, clipping limits may be set at
plus and minus 2% of the previous interval value, about the
previous interval value. For a previous interval value of 50
Nano-Amps and greater, clipping limits may be set at plus and minus
1% about the previous interval value. In alternative embodiments,
different clipping limits may be used and claimed subject matter is
not limited in this respect.
[0059] FIG. 9 shows a clipping limit example according to a
particular embodiment in which a previous interval value 500,
associated with interval N-1, has a magnitude of 13.0 Nano-Amps,
which is less than 15.0 Nano-Amps. Therefore, a maximum clipping
limit 502 for a present interval value 506 is set at 13.5
Nano-Amps, which is 0.5 Nano-Amps greater than the magnitude of the
previous interval value 500. A minimum clipping limit 504 is set at
12.5 Nano-Amps which is 0.5 Nano-Amps below the previous interval
value 500. Present interval value 506, associated with interval N,
is between the maximum clipping limit 502 and the minimum clipping
limit 504 and is therefore acceptable.
[0060] In another example shown in FIG. 9, the present interval
value 508, associated with interval M, has a value of 25.0
Nano-Amps which is outside of the clipping limit 514 and will
therefore be clipped. The previous interval value 510, associated
with interval M-1, is 26.0 Nano-Amps, which is included in the
range from 25.0 up to but not including 50.0 Nano-Amps as discussed
above. Therefore the clipping limits are +/-2%. The maximum
clipping limit 512 is 2% greater than the previous interval value
510 as follows:
26.0+26.0*0.02=26.5 Nano-Amps.
[0061] Similarly the minimum clipping limit 514 is 2% less than the
previous interval value 510 as follows:
26.0-26.0*0.02=22.5 Nano-Amps.
[0062] Since the present interval value 508 of 25.0 Nano-Amps is
less than the minimum clipping limit 514 of 25.5 Nano-Amps, it will
be clipped, and 25.5 Nano-Amps will be used in place of 25.0
Nano-Amps to calculate a memory storage value. For further
illustration, FIG. 8 shows interval value R', which is calculated
by averaging sampled values N through Q, is outside of the clipping
limits 412 and 414, which result from the previous interval value
L'. Therefore, in this particular example, the magnitude of
interval value R' is not used to calculate memory value AD'',
instead R'', which is the magnitude of the minimum clipping limit
414, is used.
[0063] In other embodiments, clipping limits may be a smaller or
larger number of Nano-Amps or a smaller or larger percentage of the
previous interval value based on the sensor characteristics
mentioned above. Alternatively, clipping limits may be calculated
as plus or minus the same percent change from every previous
interval value. Other algorithms may use several interval values to
extrapolate the next interval value and set the clipping limits to
a percentage higher and lower than the next anticipated interval
value. In further alternatives, clipping may be applied to the
sampled values, interval values, memory values, calculated glucose
values, estimated values of a measured characteristic, or any
combination of such values.
[0064] In particular embodiments, interval values are compared to
an out-of-range limit of 200 Nano-Amps. If three consecutive
interval values are equal to or exceed the out-of-range limit, the
sensor sensitivity may be deemed to be too high, and an alarm is
activated to notify the user that re-calibration is required or the
sensor may need replacing. In alternative embodiments, an
out-of-range limit may be set at higher or lower values depending
on the range of sensor sensitivities, the expected working life of
the sensor, the range of acceptable measurements, and/or the like.
In particular embodiments, an out-of range limit is applied to
sampled values. In other embodiments, an out-of-range limit is
applied to the memory storage values.
[0065] In particular embodiments, unstable signal alarm limits may
be set to detect drastic changes in memory storage values from one
to another. Signal alarm limits may be established similarly to the
clipping limits described above for the interval values, but allow
for a larger change in value since there is more time between
memory storage values than between interval values. Re-calibration
or replacement of the glucose sensor 12 may be performed once an
unstable signal alarm is activated. In essence, in a particular
implementation, such an alarm is therefore activated in the event
that glucose monitor 100 detects an unacceptable level of noise in
the ISIG from glucose sensor 12.
[0066] In a particular embodiment, a memory storage value may be
considered valid (Valid ISIG value) unless one of the following
calibration cancellation events occurs: an unstable signal alarm
(as discussed above); a sensor initialization event (as discussed
above); a sensor disconnect alarm; a power on/off event; an
out-of-range alarm (as discussed above); or a calibration error
alarm. Here, only Valid ISIG values may be used to calculate blood
glucose levels by the glucose monitor 100 or post processor 200, as
shown in FIG. 10. Once a calibration cancellation event occurs,
successive memory storage values are not valid, and therefore are
not used to calculate blood glucose, until glucose monitor 100 or
post processor 200 is re-calibrated. FIG. 10 shows an explanatory
computer screen shot in which cell P3 indicates a sensor disconnect
alarm with the abbreviation "SeDi". As shown, blood glucose values
do not appear in column K, titled "Sensor Value", and Valid ISIG
values do not appear in column J until after the sensor is
initialized, as indicated by the "ESI" flag in cell N17. One
exception however, is the power on/off event. If glucose monitor
100 is turned off for a short enough period of time, up to 30
minutes for example, memory storage values may be considered Valid
ISIG values as soon as the power is restored. If the power is off
for longer than 30 minutes, for example, glucose monitor 100 may be
re-calibrated before ISIG values are considered valid.
Alternatively, power may be off for a duration such as 30 minutes
or longer and, once power is restored, the memory storage values
may comprise Valid ISIG values. Here, a sensor disconnect alarm may
be activated if the glucose monitor 100 does not detect a signal.
In preferred embodiments, when two or more out of five interval
values collected within a given memory storage rate are less than
1.0 Nano-Amp, a disconnect alarm may be triggered. In alternative
embodiments, greater or fewer values need be below a particular
threshold current level to trigger a disconnect alarm depending of
the acceptable range or sensor readings and the stability of an
associated sensor signal. Two remaining calibration cancellation
events, the calibration error and an alternative embodiment for the
out-of-range alarm, are discussed in conjunction with the
calibration process below.
[0067] Particular implementations are directed to calibration
techniques that may be used by either glucose monitors during
real-time measurements of one or more signals from a glucose
sensor, or post processors during post-processing of data that has
been previously recorded and downloaded (as shown in FIG. 10).
[0068] To calibrate glucose monitor 100, a calibration factor
called a sensitivity ratio (SR) (blood glucose level/Valid ISIG
value) may be calculated for a particular glucose sensor 12. The SR
is a calibration factor used to measure/estimate a blood glucose
concentration based, at least in part on a Valid ISIG value
(Nano-Amps) into a blood glucose level (mg/dl or mmol/l). In
alternative embodiments, units for the SR may vary depending on the
type of signal available from the sensor (frequency, amplitude,
phase shift, delta, current, voltage, impedance, capacitance, flux,
and the like), the magnitude of the signals, the units to express
the characteristic being monitored, and/or the like.
[0069] In particular implementations, a user may obtain a blood
glucose reference reading from a common glucose meter, or another
blood glucose measuring device, and immediately enter such a blood
glucose reference reading into glucose monitor 100. Such a blood
glucose reference reading is assumed to be accurate and is used as
a reference for calibration. Glucose monitor 100, or a post
processor 200, may temporally correlate a blood glucose reference
reading with a Valid ISIG value to establish a "paired calibration
data point." Since a glucose level in an interstitial body fluid
tends to lag behind a blood glucose level, glucose monitor 100 or
post processor 200 applies a delay time and then pairs the blood
glucose reference reading with a Valid ISIG value as shown in FIG.
11. In particular embodiments, an empirically derived ten minute
delay may be used. In a particular implementation where Valid ISIG
values are averaged and stored every five minutes, glucose monitor
100 may correlate a blood glucose reference reading with the third
Valid ISIG stored in memory after the blood glucose reference
reading is entered (resulting in an effective delay of ten to
fifteen minutes in this particular example). FIG. 11 illustrates an
example, in which a blood glucose reference reading 600 of 90 mg/dl
is entered into the glucose monitor 100 at 127 minutes. The next
Valid ISIG value 602 may be stored at 130 minutes. Given a 10
minute delay, a glucose reference reading 600 may be paired with
Valid ISIG value 604 which is stored at 140 minutes with a value of
30 Nano-amps. Note that two numbers are needed to establish one
paired calibration data point, a blood glucose reference reading
and a Valid ISIG.
[0070] Other delay times may be used depending on a particular
user's metabolism, response time of the sensor, delay time incurred
for the glucose meter to calculate a reading and for the reading to
be entered into the glucose monitor 100, a type of analyte being
measured, the tissue that the sensor is placed into, environmental
factors, whether the previous glucose Valid ISIG value (or the
trend of the Valid ISIG values) was higher or lower than current
Valid ISIG value, and/or the like. Once paired calibration data is
available, the appropriate calibration process may be applied
dependent on how many paired calibration data points are available
since the last calibration, the total period of time that glucose
sensor 12 has been in use, and the number of times glucose sensor
12 has been calibrated.
[0071] In particular embodiments, blood glucose reference readings
may be entered into glucose monitor 100 periodically through out
each day of use. Here, calibration may be conducted immediately
after the initialization/stabilization of glucose sensor 12 and
once a day thereafter. However, such calibration may be conducted
more or less often depending on whether glucose sensor 12 has been
replaced, whether a calibration cancellation event has occurred,
the stability of glucose sensor 12 sensitivity over time, and/or
the like.
[0072] In preferred embodiments, blood glucose reference readings
are collected several times per day but a new calibration factor is
calculated only once per day. Therefore, typically more than one
paired calibration data point is collected between calibrations. In
alternative embodiments, the glucose monitor is calibrated every
time a new paired calibration data point is collected.
[0073] Particular embodiments may use a single-point calibration
technique (shown in a block diagram of FIG. 13) to calculate the SR
if only a single paired calibration data point is available, such
as immediately after initialization/stabilization. And a modified
linear regression technique (shown in a block diagram in FIG. 15a)
may be used if two or more paired calibration data points are
available. Particular embodiments may use a single-point
calibration technique whether or not more than one paired
calibration data point is available.
[0074] A single-point calibration equation may be based on an
assumption that a Valid ISIG will be 0 when the blood glucose is 0.
As shown in process 750 of FIG. 12, a single paired calibration
point 700 obtained at block 754 is used with the point (0,0) to
establish a line 702. The slope of the line from the origin (0,0)
and passing through the single paired calibration point 700
provides a single-point sensitivity ratio (SPSR). Here, block 756
may calculate such an SPSR as follows:
SPSR = Blood Glucose Reference Reading Valid ISIG ##EQU00001##
[0075] Therefore, the calibrated blood glucose level may be
expressed as follows:
Blood Glucose Level=Valid ISIG*SPSR
[0076] As an example, using the values of 20.1 Nano-Amps and 102
mg/dl from the paired calibration data point shown in FIG. 12,
calculation of SPSR may be expressed as follows:
SPSR=102/20.1=5.07 mg/dl per Nano-Amp
[0077] To continue with the current example, once calibration is
complete, given a glucose sensor reading of 15.0 Nano-Amps,
calculated blood glucose level may be determined as follows:
Blood Glucose Level=15.0*5.07=76.1 mg/dl
[0078] Additionally, particular embodiments may use an offset value
in a calibration equation to compensate for the observation that
more sensitive glucose sensors 12 (e.g., glucose sensors 12 that
generate higher ISIG values compared to other glucose sensors 12 at
the same blood glucose level, which result in lower SR values) may
have a less linear performance at very high blood glucose levels in
comparison to glucose sensors 12 with lower sensitivity (and
therefore relatively higher SR values). If the SPSR for a
particular glucose sensor 12, as calculated above, is less than a
sensitivity threshold value, then a modified SPSR (MSPSR) may be
calculated at block 760 using an offset value selected at block
758. In one particular implementation, the threshold value is 7. If
the initial calculation of the SPSR (shown above) is less than 7,
for example, an offset value of 3 may be used to calculate the
MSPSR. If the initial calculation of SPSR yields a value of 7 or
greater, then the offset value may be 0. Thus, the MSPSR may be
calculated at block 760 using the offset value according to a
modified single-point calibration expression, as follows:
MSPSR = Blood Glucose Reference Reading Valid ISIG - offset
##EQU00002##
[0079] Accordingly, an initial calibration of sensor 12 may be used
to estimate a blood glucose from a sensor measurement at block 762
as follows:
Blood Glucose Level=(Valid ISIG-offset)*SPSR
[0080] Continuing the above example since the SPSR is 5.07, which
is less than 7, the sensitivity ratio is recalculated using the
MSPSR equation as:
MSPSR=102/(20.1-3)=5.96 mg/dl per Nano-Amp
[0081] Given a glucose sensor reading of 15.0 Nano-Amps after
calibration, the calculated blood glucose may be expressed as
follows:
Blood Glucose Level=(15.0-3)=5.96=71.5 mg/dl
[0082] In another example, given a blood glucose reference reading
of 95 from a typical blood glucose meter and a Valid ISIG value of
22.1, a resulting SPSR may be determined as 95/22.1=4.3. Since
SR<7, the offset=3. Therefore, the MSPSR is
95/[22.1-3].apprxeq.5.0. Note that if the SPSR is greater than or
equal to 7 the offset value is 0 and therefore the MSPSR=SPSR.
[0083] In alternative embodiments, the offset value may be
eliminated from the expression for calculating the blood glucose
value as follows:
Blood Glucose Level=Valid ISIG*MSPSR
[0084] The threshold value of 7 and the associated offset of 3 have
been empirically selected based on the characteristics observed
from testing a particular type of glucose sensors 12, such as those
described in U.S. Pat. No. 5,391,250 entitled "Method of
Fabricating Thin Film Sensors", and U.S. Pat. No. 6,360,888. Other
threshold values may be used in conjunction with other offset
values to optimize the accuracy of the calculated MSPSR for various
types of glucose sensors 12 and sensors used to detect other body
characteristics. In fact, many threshold values may be used to
select between many offset values. An example using two different
threshold values (4 and 7) to select between three different offset
values (5, 3 and 0) follows: [0085] if SPSR<4, offset=5; [0086]
if 4.ltoreq.SPSR<7, offset=3; and [0087] if SPSR.gtoreq.7,
offset=0.
[0088] In particular embodiments an MSPSR may be compared to a
valid sensitivity range to determine whether a newly calculated
MSPSR is reasonable. In order to identify potential system
problems, a valid MSPSR range of 1.5 to 15 may be employed, for
example. However this is merely an example of such a range and
claimed subject matter is not limited in this respect. This range
may be determined based, at least in part, upon valid glucose
sensor sensitivity measurements made in-vitro. MSPSR values outside
this range may result in a calibration error alarm (CAL ERROR) to
notify the user of a potential problem. Other valid sensitivity
ranges may be applied depending on the types of sensors to be
calibrated, the range of acceptable sensitivity levels for the
various sensor types, the manufacturing consistency expected for
the sensors, environmental conditions, how long the sensor has been
in use, and/or the like.
[0089] Particular embodiments may augment the above described
single-point calibration technique using a modified linear
regression technique (shown in a block diagram in FIG. 15a) if more
than one paired calibration data point is available. As shown in
FIG. 14, paired calibration data points 800 may linearly regressed
by a least squares method to calculate a best fit straight line 802
correlated with paired calibration data points 800. The slope of
the line resulting from the linear regression may be the linear
regression sensitivity ratio (LRSR) used as the calibration factor
to calibrate the glucose monitor 100.
[0090] Linear and nonlinear least squares regression may apply an
assumption that each data point provides equal information about a
deterministic part of a total variation in a value or outcome. In
such processes a standard deviation of an error associated with a
value would be constant for all estimated predictions, for example.
In some processes this is not the case. For example, in real-time
continuous glucose monitoring using an enzymatic minimally invasive
biosensor to estimate plasma glucose concentrations as discussed
above, an unequal error distribution may exist. Here, a scatter
plot of FIG. 15b illustrates several calibrated glucose sensor
points plotted against paired blood glucose reference values
throughout a large glycemic range in one particular implementation.
It can be observed from the plot that the accuracy of the sensor
glucose measurements decreases as the reference blood glucose
values increase. Such a decreasing accuracy may be measured as
variance and/or standard deviation of an error associated with such
measurements that increases with blood glucose concentration and/or
paired reference blood glucose reference value. Accordingly, in
certain circumstances it may be advantageous not to treat every
observation equally, and apply a weighted least squares regression,
for example. This may be implemented according to a particular
embodiment by giving each point an appropriate weight to control an
amount of influence over parameter determination. In doing this,
points with less precise influence may be weighted less in
computing a linear regression, while points with more influence may
be more heavily weighted.
[0091] In a particular implementation, paired calibration points,
comprising sample values associated with blood-glucose
concentration sensor measurements paired with reference
measurements at block 852, may be linearly regressed at block 854
to determine an LRSR. As pointed out above, in particular
embodiments, such a regression may weight particular pairs and/or
sample values according to a degree of certainty associated with
the accuracy of such sample values based upon a priori information.
Such a linear regression calibration may be computed as
follows:
LRSR = i = 1 N .alpha. i .beta. i isig i BG i i = 1 N .alpha. i
.beta. i isig i 2 ##EQU00003##
[0092] where: [0093] isig.sub.i is a value representing a sensor
measurement of a blood glucose concentration for paired calibration
point i;
[0094] .alpha..sub.i is weighting applied to paired calibration
point i based upon the time that the associated sample was
obtained; [0095] BG.sub.i is reference sample of a blood glucose
concentration for paired calibration point i; [0096] .beta..sub.i
is a weighting applied to paired calibration point i based upon a
degree of certainty associated with accuracy of isig.sub.i as a
measurement of blood glucose concentration; and [0097] N is a
number of paired calibration data points which are to be linearly
regressed.
[0098] Accordingly, an estimate of a calibrated blood glucose level
may be expressed as follows:
Blood Glucose Level=Valid ISIG*LRSR
[0099] In a particular implementation, a paired calibration point
may be weighted according to a time associated with when associated
sensor measurements and reference values are obtained. Here, for
example, pairs based on more recent measurements and reference
values may be associated with an error with a smaller variance than
pairs based on measurements and reference values obtained in the
more distant past. Accordingly, the weight .alpha..sub.i applied to
calibration pairs may decrease the more distant in the past such
calibration pairs are obtained.
[0100] Also, as pointed out above, variances associated with
measurement errors in calibrating continuous glucose monitors may
not be constant across a dynamic range of blood glucose values.
Here, in one particular embodiment, weighting .beta..sub.i may
represent an inverse variance weighting. In other words,
contribution of each data point may be weighted with the inverse of
the variance for that set of blood glucose values. For example, a
set of sensor current values were paired (N=90,000 points) and the
inverse variance of sensor current calculated for each blood
glucose reference value as follows:
.beta..sub.i=[var(isig.sub.i)].sup.-1
[0101] Here, application of such an inverse variance to calibration
pairs to weight samples for linear regression is merely one example
of how such calibration pairs may be weighted based upon a
decreasing accuracy of sensor measurements, and claimed subject
matter is not limited in this respect. Furthermore, it should be
understood that a variance or standard deviation are merely
examples of how a statistical dispersion of sensor measurement
errors may be quantified, and that other metrics may be used. In
alternative embodiments, for example, .beta..sub.i may be derived
as the inverse of an estimate or approximation of the variance of
isig.sub.i. Also, as discussed below, appropriate weights may be
derived from other functions for determining a weight based, at
least in part, on blood glucose reference samples and/or blood
glucose concentration.
[0102] In this particular implementation, however, .beta..sub.i
represents an inverse variance and/or standard deviation of all
sensor samples (isig.sub.i) measured at a time corresponding to
when reference blood glucose sample values i were acquired. In one
particular example, inverse variance weights are plotted in FIG.
15c for blood glucose values ranging from 40-400 mg/dL. Again, it
should be understood, however, that the use of an inverse variance
is merely one example of how calibration pairs may be weighted
based upon a degree of certainty associated with accuracy of sensor
measurements and claimed subject matter is not limited in this
respect.
[0103] Alternatively, weights (for application to calibration pairs
in a linear regression) may be obtained from a function based on an
inverse variance weights. Here, use of such a function may provide
a high quality estimate that removes noise present in the inverse
variance weights arising from sources such as, for example,
variability between blood-glucose and a blood glucose monitor. This
is illustrated in FIG. 15d where a best line fit is produced by
regressing the square root of the variance or standard deviation.
For the particular example of sensor measurement samples shown in
FIG. 15b, weights may be determined according to the corresponding
function derived from such a best line fit as follows:
w i = 1 ( 1.787 + 0.0291 i ) 2 ##EQU00004##
[0104] FIG. 15e shows a plot of inverse variance .beta..sub.i and
function derived from such a best line fit of variance/standard
deviation as a function of ISIG weights w, over a range of blood
glucose concentration range from 0 to 400 mg/dl. An inverse
variance is plotted as 902 while a weighting function is plotted as
900. As can be observed, the weighting function 900 removes noise
in the inverse variance to provide a weighting function to be
applied to calibration pairs that is a decreasing function of blood
glucose concentration and/or associated blood sample reference
values associated with such calibration pairs.
[0105] It should be observed that this particular linear regression
uses a fixed intercept of zero. In other words, if the Valid ISIG
is 0 the blood glucose value is 0. Accordingly, this particular
linear regression method estimates only one regression parameter,
the slope. In alternative embodiments, other linear regression
methods may be used that estimate additional regression parameters
such as an offset value.
[0106] At block 856, particular embodiments may select an offset
value for use in calculating a modified linear regression
calibration. The purpose of such an offset value, as described
above for the single-point calibration, is to compensate for an
observation that more sensitive glucose sensors 12 may have a less
linear performance at very high blood glucose levels. If an LRSR
for a particular glucose sensor 12, as calculated in the linear
regression calibration expression above, is less than a sensitivity
threshold value, then a modified linear regression sensitivity
ratio (MLRSR) may be calculated using an offset value included in a
modified linear regression calibration expression. In one
particular embodiment, for example, such a sensitivity threshold
may be 7. Here, if an initial calculation of an LRSR is less than
7, an offset value of 3 may be used to calculate an MLRSR. If an
initial calculation of LRSR yields a value of 7 or greater, an
offset value of 0 may be used. Thus, MLRSR may be calculated at
block 858 using the selected offset value in the modified linear
regression calibration according to the following expression:
MLRSR = i = 1 N .alpha. i .beta. i [ isig i - offset ] BG i i = 1 N
.alpha. i .beta. i [ isig i - offset ] 2 ##EQU00005##
[0107] Accordingly, a calculated blood glucose level may be
estimated at block 860 as follows:
Blood Glucose Level=(Valid ISIG-offset)*MLRSR
[0108] Just as in the case of single-point calibration techniques
described above, other threshold values may be used at block 856 in
conjunction with other offset values in the modified linear
regression calibration equation to optimize the accuracy of the
calculated MLRSR for various types of glucose sensors 12 and other
characteristic sensors.
[0109] In particular embodiments, a newly calculated MLRSR may be
compared to a valid sensitivity range to determine whether the
newly calculated MLRSR is reasonable. To identify potential system
problems, a valid MLRSR range of 2.0 to 10.0 may be employed. MLRSR
values outside this range may result in a calibration error alarm
(CAL ERROR) to notify a user of a potential problem. As described
above for the single-point calibration techniques, other valid
sensitivity ranges may be applied.
[0110] In particular embodiments, glucose monitor data (e.g.,
paired calibration data points as discussed above) may be linearly
regressed over a 24 hour period (or window), and new sensitivity
ratios may be used for each 24 hour time period. In other
embodiments, a time period may be reduced to only a few hours or
enlarged to cover the entire monitoring period with the glucose
sensor (e.g., several days--or even weeks with implanted sensors).
In further embodiments, such a time window may be fixed at a
predetermined size, such as 24 hours, 12 hours, 6 hours, and/or the
like, and the window is moved along over the operational life of
the sensor.
[0111] In particular embodiments, paired calibration data points
from measurements taken before the last calibration may be used to
calculate a new sensitivity ratio. For example, to calibrate the
glucose monitor every 6 hours, a paired calibration data point may
be established every 6 hours. A linear regression technique
described above may be executed using four paired calibration data
points, the most recently acquired point and points obtained from
six, twelve and eighteen hours before. Alternatively, a number of
paired calibration data points used in the calibration may be as
few as one or as large as the total number of paired calibration
data points collected since the glucose sensor was installed. In
alternative embodiments, a number of paired calibration data points
used in a calibration computation may grow or shrink during the
life of the glucose sensor due to glucose sensor anomalies.
[0112] In still other embodiments, decay characteristics of glucose
sensor 12 over time may be factored into the equation to account
for known degradation characteristics of glucose sensor 12 due to
site characteristics, enzyme depletion, body movement, and/or the
like. Considering these additional parameters in the calibration
equation may more accurately tailor calibration computations used
by the glucose monitor 100 or post processor 200. In particular
embodiments, other parameters may be measured along with the blood
glucose such as, temperature, pH, salinity, and/or the like. These
other parameters may be used to calibrate the glucose sensor using
non-linear techniques.
[0113] In a particular embodiment, real-time calibration adjustment
can be performed to account for changes in the sensor sensitivity
during the lifespan of the glucose sensor 12 and to detect when a
sensor fails. FIG. 16 (in conjunction with FIGS. 17, 18a and 18b)
describes the logic of a self-adjusting calibration technique to
adjust the calibration formula or detect a sensor failure in
accordance with one particular implementation.
[0114] At block 1000, a user may obtain a blood glucose reference
from a common glucose meter, or another blood glucose measuring
device, and immediately enter the blood glucose reference reading
into glucose monitor 100. For every such meter blood glucose entry,
an instantaneous calibration check may be performed and compared to
an expected range of the value of the calibration check, as in
block 1010. In particular embodiments, a Calibration Factor current
is calculated (e.g., CFc=Meter BG/current ISIG value) to determine
if the CFc (Calibration Factor current) ratio is between 1.5 to 12
("Criteria 1"), one criterion for an accurate ISIG value in a
particular implementation. If data is outside this range, raising a
likelihood of a sensor failure or incorrect determination/entry of
a meter BG value, a Cal Error alarm may be triggered at block 1030
and the Recalibration Variable (Recal), which is originally set at
NOFAIL may be changed to FAILC1. At this point, another blood
glucose reference reading may be requested and entered into the
glucose monitor 100 to determine whether there was indeed a sensor
failure or the Meter Blood Glucose value was incorrectly inputted.
The previous Metered Blood Glucose value that generated the error
can be thrown out completely. If Criteria 1 is again not satisfied
at block 1010, an end of the sensor life message may be generated
at block 1040 since then the Recal variable would be recognized as
FAILC1 at block 1020. However, if Criteria 1 is met at block 1010,
then block 1200 may determine whether the Recal variable is not
equal to FAILC2. Here, the Recal variable is set to FAILC2 only if
Criteria 2a is not met, which is discussed below: Given that the
Recal variable at this point may only be set to a NOFAIL or FAILC1,
logic proceeds to block 1210.
[0115] Block 1210, a check is performed to determine whether an
existing calibration slope estimation (Previous Estimated Slope or
PES) is much different from the CFc performed using a new meter
blood glucose value. A significant difference may indicate a sensor
failure, for example. In a particular embodiment, a difference
between a previous estimated slope (PES) and a CFc in terms of
percentage (threshold 1) and mg/dl (threshold 2) may be performed.
Thresholds 1 and 2 may be set depending on particular sensor
characteristics. In a particular implementation, an example of
checking such changes between the PES and CFc may be performed as
follows:
|1-PES/CFc|*100>threshold 1; and
|CFc-PES|*isig>threshold 2.
[0116] If threshold 1 and/or threshold 2 are exceeded according to
the above expressions (collectively "Criteria 2a"), then depending
on the Recal variable (at block 1220), either trigger an end of
sensor message may be triggered at block 1040 (if the Recal
variable is equal to FAILC1 or FAILC2 at block 1220) or a Cal Error
alarm may be generated at block 1230 (if the Recal variable is
equal to NOFAIL at block 1220). Here, if a Cal Error alarm is
generated at block 1230, the Recal variable may be set to FAILC2,
the current meter blood glucose reading will be stored as MBGp
(Meter Blood Glucose previous), and another blood glucose reference
is requested and entered into the glucose monitor 100 (as MBGc) at
block 1000. By requesting a new meter blood glucose reading, a
comparison can be made between the last meter blood glucose reading
stored at block 1230, and the new meter blood glucose reading
entered at block 1000 may be used to determine whether there was a
sensor failure. The logic follows the same paths as described above
after block 1000 until the logic reaches block 1200. At block 1200,
since Recal variable is now set to FAILC2 at block 1230, a
difference between the previous calibration check (CFp), which
generated the FAILC2 alert, and the CFc is performed at block 1300.
In particular implementations, the difference between the previous
calibration check and the current calibration check in terms of
percentage (threshold 1) and mg/dl (threshold 2) may also be
performed. In addition, a check is performed to determine whether
there has been a directional change between the CFp and CFc
(collectively "criteria 2b"). An example of criteria 2b may be
expressed as follows:
|1-CFp/CFc|*100>threshold 1;
|CFc-CFp|*Isig>threshold 2; and
(CFp-PES)*(CFc-CFp)>0.
[0117] If the percentage and absolute difference exceeds threshold
1 and threshold 2, and there is no directional change in the slope
with the second blood glucose meter reading, then an end of sensor
message will be triggered at block 1040. If criteria 2b is met,
then the logic proceeds to block 1310. At block 1310, the logic
then determines whether the difference between the previous value
and the current value was due to a change in sensitivity of the
sensor or whether the reading is merely noise. In the preferred
embodiment, the determination of change in sensitivity versus noise
is made by using Criteria 3b. Criteria 3b compares the difference
between (the PES and CFc) and (the CFp versus the CFc) at block
1420. For example:
|PES|CFc|<|CFp|CFc|
[0118] As illustrated in FIG. 17a, if a difference between PES and
CFc is less than a difference between CFp and CFc, criteria 3b will
be met, indicating that the previous CFp is an outlier reading
(e.g., an anomaly). Then, the MBGp (Meter Blood Glucose previous)
is removed at block 1320 and only the MBGc paired with a valid ISIG
is used in the slope calculation, which is resumed at block 1430
and applied in interpreting the sensor readings at block 1130.
[0119] As illustrated in FIG. 17b, if criteria 3b shows that a
difference between the PES and CFc is greater than a difference
between CFp and CFc, criteria 3b would not be met, indicating a
change in sensor sensitivity. A slope calculation may then be
fine-tuned by creating a new (artificial) meter blood glucose value
(MBGN) with a paired ISIG according to the last slope (Seeding) at
block 1330. Using the new paired MBG (MBGN) with the paired MBGp
and MBGc, the slope calculation may be restarted (or reset) at
block 1340, as seen in FIG. 17b. Sensor calculation may then be
performed using a new slope calculation at block 1130. By resetting
a slope calculation, such a slope calculation can thus be modified
automatically to account for changes in sensor sensitivity.
[0120] Continuing the logic from block 1210, if the percentage
and/or absolute difference between the PES and CFc is within
threshold 1 and/or threshold 2 at block 1210, indicating a valid
calibration, the Recal variable is again checked at block 1400. If
the Recal variable is equal to FAILC1 (indicating that the meter BG
was checked twice), any fine-tuning determination may be skipped
and the MBGc may be paired with a valid ISIG for use in updating a
slope calculation at block 1430 and applied in interpreting sensor
readings at block 1130. If the Recal Variable is not equal to
FAILC1, then the logic may decide whether fine-tuning the slope
calculation is needed at blocks 1410 and 1420. In particular
embodiments, a decision to fine-tune may be first made by comparing
a percentage and/or absolute difference between the PES and CFc (as
done in block 1210) with a threshold 3 and/or a threshold 4
("Criteria 4") at block 1410 as follows:
|1-PES/CFc|*100<threshold 3; and
|CFc-PES|*isig<threshold 4.
[0121] Again, threshold 3 and 4 may be determined based, at least
in part, on particular sensor characteristics. If a percentage
and/or absolute difference between PES and CFc is less than
threshold 3 and/or threshold 4 at block 1410 (i.e. Criteria 4 met),
then the slope calculation can simply be updated with the new MBGc
and paired ISIG value at block 1430, and applied in interpreting
the sensor readings at block 1130.
[0122] On the other hand, if the Criteria 4 is not met at block
1410, block 1420 may determine whether the difference between the
expected value and the current value was due to a change in
sensitivity of the sensor or whether the reading is merely noise.
In one particular implementation, such a determination of change in
sensitivity versus noise may be made by using Criteria 3a. Here,
criteria 3a CFc and a CFp at block 1420 as follows:
|PES-CFp|<|CFc-CFp|
[0123] As seen in FIG. 18a, if the difference between a PES and CFp
is less than a difference between CFc and the CFp, criteria 3a may
be met, indicating that an error between predicted and actual
values for the CFc was due to noise in previous calibrations or
beginning of a change in sensor sensitivity which may be picked up
in a subsequent calibration cycle. Slope calculation may then be
updated with a new paired blood glucose entry (MBGc) at block 1430
and applied in interpreting sensor readings at block 1130.
[0124] As seen in FIG. 18b, if criteria 3a shows that a difference
between the PES and the previous valid calibration check is greater
than a difference between the previous valid CFp and the CFc,
criteria 3b would not be met, indicating a change in the sensor
sensitivity and fine tuning is performed. Here, such fine tuning
may be performed if two MBG entries in succession indicate a change
in slope. Slope calculation may be fine-tuned by creating a new
(artificial) MBGN with a paired ISIG according to the last slope
(Seeding) at block 1330. Using such a new paired MBGN with the
paired MBGp and MBGc, a slope calculation may be restarted (or
reset) at block 1340, as seen in FIG. 18b. The sensor calculation
may then be performed using the new slope calculation at block
1130. Again, by resetting the slope calculation, the slope
calculation can thus be modified automatically to account for
changes in sensor sensitivity.
[0125] Although the above description described the primary
calibration techniques in particular embodiments, many
modifications can be made to the above described calibration
techniques without deviating from claimed subject matter. For
example, in alternative embodiments, a calibration factor may be
calculated by first using a single-point technique to calculate an
MSPSR for each paired calibration data point, and then averaging
them together, either unweighted or weighted by temporal order of
by elapsed time.
[0126] As discussed above, particular embodiments described herein
utilize a least squares linear regression computation to calibrate
the glucose monitor 100 and/or analyze sensor data using
post-processor 200, for example. However, alternative embodiments
may utilize a multiple component linear regression computation with
more variables than just the paired calibration data points
discussed above, to account for additional calibration effecting
parameters, such as environment, an individual user's
characteristics, sensor lifetime, manufacturing characteristics
(such as lot characteristics), deoxidization, enzyme concentration
fluctuation and/or degradation, power supply variations, and/or the
like.
[0127] In particular implementations, after a first calibration is
performed on a particular glucose sensor 12, subsequent
calibrations may employ a weighted average using a sensitivity
ratio (SPSR, MSPSR, LRSR, or MLRSR) calculated from data collected
since the last calibration, and previous sensitivity ratios
calculated for previous calibrations. Here, an initial sensitivity
ratio (SR1) may be calculated immediately after
initialization/stabilization using a paired calibration data point,
and used by glucose monitor 100 or post processor 200 until a
second sensitivity ratio (SR2) is calculated. Here, second
sensitivity ratio SR2 may comprise an average of SR1 and the
sensitivity ratio as calculated using the paired calibration data
points since the initial calibration (SRday1) as follows:
SR 2 = SR 1 + SR day 1 2 ##EQU00006##
[0128] The third sensitivity ratio (SR3) is an average of SR2 and
the sensitivity ratio as calculated using the paired calibration
data points since the second calibration (SRday2). The equation is
as follows:
SR 3 = SR 2 + SR day 2 2 ##EQU00007##
[0129] Sensitivity ratios for successive days may be similarly
determined as follows:
SR n = SR ( n - 1 ) + SR day ( n - 1 ) 2 , ##EQU00008##
[0130] where: [0131] SR.sub.n is the new sensitivity ratio
calculated at the beginning of time period, n, using data from time
period (n-1), to be used by glucose monitor 100, to convert Valid
ISIGs measurement values to blood glucose readings throughout time
period n; [0132] SR.sub.(n-1) is a previous sensitivity ratio
calculated at the beginning of time period n-1, using data from
time period n-2; and [0133] SRday.sub.(n-1) is the sensitivity
ratio calculated using paired calibration data points collected
since the last calibration.
[0134] Alternatively, previous sensitivity ratios may be ignored
and SR may be calculated using only the paired calibration data
points since the last calibration. In another alternative, all
previous SRs may be averaged with the latest SR calculated using
only the paired calibration data points since the last calibration.
In other implementations, the paired calibration data points are
used to establish an equation for a curve representing SR over
time. The curve may then used to extrapolate SR to be used until
the next paired calibration data point is entered.
[0135] In embodiments that use a post processor 200 to evaluate a
sensitivity ratio, such a sensitivity ratio may be calculated using
paired calibration data points over a period of time since a last
calibration, and is not averaged with previous sensitivity ratios.
A sensitivity ratio determined for a period of time may then be
applied to the same period of time over which the paired
calibration data points were collected. This may result in a more
accurate than the real-time case described above for the glucose
monitor 100 because, in the real-time case, sensitivity ratios from
a previous time period must be used to calculate the blood glucose
level in the present time period. If the sensitivity ratio has
changed over time, estimation of blood glucose using an old
sensitivity ratio may introduce an error.
[0136] In particular embodiments, once calibration is complete,
Valid ISIG values may be converted to blood glucose readings based
on a particular version of the sensitivity ratio, and the resulting
blood glucose readings are compared to an out-of-range limit. If
such a resulting calculated blood glucose level is greater than a
maximum out-of-range limit of 200 mg/dl (or equivalently 3600
mmol/l), the out-of-range alarm is activated. This is a calibration
cancellation event, therefore, ISIG values are no longer valid once
this alarm is activated. Blood glucose readings are either not
calculated, or at least not considered reliable, until the glucose
monitor 100 or post processor 200 is re-calibrated. The user may be
notified of the alarm and that re-calibration is needed.
[0137] In alternative embodiments, higher or lower maximum
out-of-range limits may be used depending on the sensor
characteristics, the characteristic being measured, the user's body
characteristics, and the like. In particular implementations, a
minimum out-of-range limit may be used or both a maximum and a
minimum out-of-range limits may be used. In other particular
embodiments, such out-of-range limits may not cause blood glucose
readings to become invalid and/or re-calibration is not required;
however, an alarm could still be provided. In additional particular
embodiments, an alarm may be activated in response to two or more
ISIG values exceeding an out-of-range limit. ISIG values that are
out-of-range may be omitted from display.
[0138] In alternative embodiments, calibration may be conducted by
injecting a fluid containing a known value of glucose into the site
around the glucose sensor set 10, followed by sending one or more
glucose sensor readings to glucose monitor 100. The readings may
then be processed (filtered, smoothed, clipped, averaged, and/or
the like) and used along with the known glucose value to calculate
the SR for the glucose sensor 12. Particular alternative
embodiments may use a glucose sensor set of the type described in
U.S. Pat. No. 5,951,521 entitled "A Subcutaneous Implantable Sensor
Set Having the Capability To Remove Or Deliver Fluids To An
Insertion Site".
[0139] In other alternative embodiments, glucose sensor 12 may be
supplied with a vessel containing a solution with a known glucose
concentration to be used as a reference, and glucose sensor 12 is
immersed into the reference glucose solution during calibration.
Glucose sensor 12 may be shipped in the reference glucose solution,
for example. As described above, glucose sensor readings may be
used to calculate a sensitivity ratio given a known (or
independently measured) glucose concentration of the solution.
[0140] In another alternative embodiment, glucose sensors 12 may be
calibrated during a manufacturing process. Sensors from the same
manufacturing lot have similar properties may be calibrated using a
sampling of glucose sensors 12 from the population and a solution
with a known glucose concentration. A sensitivity ratio is provided
with the glucose sensor 12 and is entered into glucose monitor 100
or post processor 200 by the user or another individual.
[0141] In addition, although the particular process of FIG. 18
includes specific operations occurring in a particular order, in
alternative embodiments, certain of these operations may be
performed in a different order, modified, or removed while not
deviating from claimed subject matter. Moreover, other operations
may be added to and/or combined with the above described process
without deviating from claimed subject matter. For example,
although in the particular embodiment of FIG. 16 the variable Recal
is never reset to no fail, potentially, an additional operation may
be added to reset Recal to no fail if no cal error alarms are
triggered after a predetermined number of calibrations.
[0142] Unless specifically stated otherwise, as apparent from the
following discussion, it is appreciated that throughout this
specification discussions utilizing terms such as "processing",
"computing", "calculating", "determining", "estimating",
"selecting", "weighting", "identifying", "obtaining",
"representing", "receiving", "transmitting", "storing",
"analyzing", "creating", "contracting", "associating", "updating",
or the like refer to the actions or processes that may be performed
by a computing platform, such as a computer or a similar electronic
computing device, that manipulates or transforms data represented
as physical, electronic or magnetic quantities or other physical
quantities within the computing platform's processors, memories,
registers, or other information storage, transmission, reception or
display devices. Accordingly, a computing platform refers to a
system or a device that includes the ability to process or store
data in the form of signals. Thus, a computing platform, in this
context, may comprise hardware, software, firmware or any
combinations thereof. Further, unless specifically stated
otherwise, a process as described herein, with reference to flow
diagrams or otherwise, may also be executed or controlled, in whole
or in part, by a computing platform.
[0143] It should be noted that, although aspects of the above
system, method, or process have been described in a particular
order, the specific order is merely an example of a process and
claimed subject matter is of course not limited to the order
described. It should also be noted that the systems, methods, and
processes described herein, may be capable of being performed by
one or more computing platforms. In addition, the methods or
processes described herein may be capable of being stored on a
storage medium as one or more machine readable instructions, that
if executed may enable a computing platform to perform one or more
actions. "Storage medium" as referred to herein relates to media
capable of storing information or instructions which may be
operated on, or executed by, by one or more machines. For example,
a storage medium may comprise one or more storage devices for
storing machine-readable instructions or information. Such storage
devices may comprise any one of several media types including, for
example, magnetic, optical or semiconductor storage media. For
further example, one or more computing platforms may be adapted to
perform one or more of the processed or methods in accordance with
claimed subject matter, such as the methods or processes described
herein. However, these are merely examples relating to a storage
medium and a computing platform and claimed subject matter is not
limited in these respects.
[0144] While there has been illustrated and described what are
presently considered to be example features, it will be understood
by those skilled in the art that various other modifications may be
made, and equivalents may be substituted, without departing from
claimed subject matter. Additionally, many modifications may be
made to adapt a particular situation to the teachings of claimed
subject matter without departing from the central concept described
herein. Therefore, it is intended that claimed subject matter not
be limited to the particular examples disclosed, but that such
claimed subject matter may also include all aspects falling within
the scope of appended claims, and equivalents thereof.
* * * * *